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HIV and T Follicular Helper Cells: a Dangerous Relationship

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HIV and T Follicular Helper Cells: a Dangerous Relationship HIV and T follicular helper cells: a dangerous relationship Carola G. Vinuesa J Clin Invest. 2012;122(9):3059-3062. https://doi.org/10.1172/JCI65175. Commentary HIV infection leads to progressive destruction of infected CD4 T cells, hypergammaglobulinemia, and loss of memory B cells. Germinal centers, which are key to memory B cell formation and protective antibody responses, are major HIV reservoirs in which the virus replicates within T follicular helper (TFH) cells. In this issue of the JCI, the Koup and Streeck groups report that chronic SIV/HIV infection promotes TFH cell accumulation, which may drive B cell dysregulation. Their discoveries suggest that HIV harnesses TFH cells to evade the antibody response. Find the latest version: https://jci.me/65175/pdf commentaries HIV and T follicular helper cells: a dangerous relationship Carola G. Vinuesa Department of Pathogens and Immunity, John Curtin School of Medical Research, Australian National University, Canberra, Australia. HIV infection leads to progressive destruction of infected CD4 T cells, HIV infects and expands TFH cells hypergammaglobulinemia, and loss of memory B cells. Germinal centers, It has been known since the late 1980s which are key to memory B cell formation and protective antibody respons- that germinal centers constitute the larg- es, are major HIV reservoirs in which the virus replicates within T follicular est reservoirs of HIV virions (9), which are helper (TFH) cells. In this issue of the JCI, the Koup and Streeck groups retained in the form of immune complexes report that chronic SIV/HIV infection promotes TFH cell accumulation, on the processes of follicular dendritic cells which may drive B cell dysregulation. Their discoveries suggest that HIV (FDCs) (10). It has also been suggested that harnesses TFH cells to evade the antibody response. active viral infection occurs primarily at these sites during clinical latency (11). Viral Antibodies play an essential role in the pro- cells along two separate routes. An extra- replication does not occur in FDCs them- tection against viral infection, acting through follicular pathway generates short-lived, selves, but rather in germinal center CD4 different effector mechanisms to prevent viral low-affinity plasmablasts, whereas the T cells, now known as TFH cells (12–14). entry into host cells and eliminate infected follicular route gives rise to specialized TFH susceptibility to SIV infection is also cells. A few viruses, however, have evolved microenvironments called germinal cen- confirmed in the current study by Petrovas sophisticated mechanisms to evade the neu- ters, in which affinity maturation of the and colleagues (5). There have even been tralizing antibody response and therefore antibody response takes place (7). Within suggestions that HIV-1 may replicate more persist. In the case of HIV-1, multiple mecha- germinal centers, antigen-specific B cells actively in germinal center TFH cells com- nisms enable it to evade antibody binding acquire random point mutations targeted pared with that in other CD4 T cells (15). and replicate at leisure. These mechanisms at the Ig V region genes that change the In the context of murine LCMV infection, include the death of virus-specific CD4 T cells specificity of the B cell receptor. Those B viral persistence promotes the accumula- that are required to help the B cell response, cells that consequently bind antigen with tion of TFH cells in mouse secondary lym- a high mutation rate that allows the rapid higher affinity are thought to gain com- phoid tissues, which helps control infec- emergence of antigenic escape variants, and a petitive advantage to receive selection sig- tion (16). Now three groups also report structure of the envelope complex that makes nals from specialized TFH cells. Selected TFH cell accumulation during SIV and HIV conserved epitopes relatively inaccessible to B cells terminally differentiate into long- infection. Petrovas et al. observed that the antibodies (1, 2). In addition to preventing lived memory B cells or memory plasma proportion of TFH cells was increased by otherwise effective antibodies from inhibit- cells that home to the bone marrow (7). approximately 8 fold in 50% of chronically ing virus entry into cells, HIV can also alter Despite the described resistance of HIV SIV-1–infected rhesus macaques (RMs) — the quality of the antibody response: chronic to antibody-mediated neutralization, designated “TFHhi” — compared with that HIV infection is associated with hypergam- up to 25% of HIV-1–infected individuals in uninfected or acutely infected RMs or maglobulinemia, poor antibody responses to manage to develop high titers of broadly the “TFHlo” group of chronically infected protein vaccines, and decreased antigen-spe- neutralizing antibodies over time. The RMs (5). Hong and colleagues enumerated cific memory B cells (reviewed in ref. 3). The high-affinity human antibody VRC01, TFH cells per unit area of lymph node sec- studies in this issue of the JCI by Lindqvist which recognizes the initial site of CD4 tions; an approximately 4-fold increase in et al. (4) and Petrovas et al. (5), together with a attachment on HIV-1 GP120 and neutral- TFH cells was also observed in chronically parallel study by Hong et al. (6), suggest that izes about 90% of HIV-1 isolates, appears infected macaques compared with that in accumulation of T follicular helper (TFH) to evolve from a low-affinity unmutated uninfected or acutely infected ones (6). cells, together with possibly altered function germline ancestor via the acquisition of These results suggest an increase in TFH during chronic HIV infection, may be at the a vast number — 70 to 90 — of somatic cells in absolute numbers, as opposed to root of this form of humoral evasion. mutations (8). This represents around a a lower rate of depletion compared with 4-fold higher frequency of changes than other CD4 T cell subsets. In the study by Germinal center origin of protective those typically observed during the affin- Lindqvist et al., HIV-infected individuals anti-HIV antibodies ity maturation process. These and other had approximately 10-fold higher frequen- B cells that receive cognate T cell help can data have suggested a germinal center cies of TFH cells compared with those of differentiate into antibody-producing origin and TFH-mediated selection of uninfected subjects (4). This is in itself broadly neutralizing antibodies and raise quite extraordinary since HIV kills the the possibility that altered selection in vast majority of cells it infects (17), and, Conflict of interest: The author has declared that no conflict of interest exists. germinal centers may contribute to the as discussed above, TFH cells themselves Citation for this article: J Clin Invest. 2012; failure to generate protective antibodies are susceptible to infection. None of the 122(9):3059–3062. doi:10.1172/JCI65175. in infected individuals. groups observed a correlation between The Journal of Clinical Investigation http://www.jci.org Volume 122 Number 9 September 2012 3059 commentaries Figure 1 Potential mechanisms by which TFH cells drive B cell dysregulation and constitute privileged virus reservoirs in HIV infection. (i) Excessive IL-6 produced by FDCs that harbor HIV viruses leads to upregulation of BCL-6 and increased differentiation and/or maintenance of TFH cells. Increased TFH cell numbers, together with abundant antigen, lowers competition for B cell selection reducing affinity maturation. (ii) Chronic virus infection changes the TFH cell expression of key molecules, including BCL6, IL6RA, IL4, LIGHT, and TGIF1, leading to altered function that may contribute to decreased memory B cell formation. (iii) In HIV-infected individuals, a larger fraction of TFH cells secrete IL-21 and possibly other cytokines known to promote B cell differentiation and antibody production; this can contribute to the hypergammaglobulinemia. (iv) The high IL-6 levels found in HIV infection may directly promote plasmacytosis and even enhance differentiation of memory B cells into plasma cells, leading to hypergammaglobulinemia and loss of memory B cells. (v) HIV replicates in TFH cells, and this may be enhanced by FDC-derived cytokines, including TNF. Exposure to high levels of IL-6 might also explain the increased proliferative rate of TFH cells in infected individuals, which may help maintain the viral reservoirs. (vi) It has been suggested that infection of TFH cells may be a strategy for viral persistence, since germinal centers are relatively devoid of cytolytic CD8+ T cells. GC, germinal center. 3060 The Journal of Clinical Investigation http://www.jci.org Volume 122 Number 9 September 2012 commentaries HIV-1 plasma viral load and TFH cell num- with that in treated individuals (4). It is the TFH cell expansion seen in chronic bers, although it is possible that such cor- therefore possible that excess of this and HIV infection is beneficial or detrimental relation might exist with tissue virus levels; other TFH-derived cytokines, such as IFN-γ in mounting a high-affinity, broadly neu- virus is known to persist in tissues even and IL-10, contributes to hypergamma- tralizing antibody response against HIV in when it is undetectable in the blood (18). globulinemia (Figure 1, iii). Furthermore, humans. TFH cell expansion was shown to What drives the TFH cell accumulation the increased amounts of IL-6 found in help control chronic LCMV viral infection in chronic HIV infection? First, TFH cells chronic HIV infection are likely to increase in mice (16) and correlate with production extracted from HIV-infected individuals plasma cell survival and thus augment of high-affinity anti-SIV IgG antibodies in expressed more BCL-6 — the transcription total IgG levels (Figure 1, iv). macaques (5). However, finding that the factor required for TFH formation and Another intriguing observation was the TFH cell expansion in humans favored maintenance (19) — than those from treat- inverse correlation between the proportion accumulation of GAG-specific rather ed or uninfected subjects (4) (Figure 1, i).
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